Exploiting synthetic-lethal interactions to target triple-negative breast cancers

利用合成致死相互作用来靶向三阴性乳腺癌

• 批准号: 8487128
• 负责人: Dai Horiuchi
• 金额: $ 11.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487128
• 关键词: Apoptosis; Apoptotic; Automobile Driving; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; Biological; Biology; Breast Cancer Cell; CDC2 Protein Kinase; Cancer cell line; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Critiques; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Diversity Library; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptors; Family member; Genetic; Human; Individual; Knowledge; Lead; Lymphoma; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mammary gland; Mentors; Messenger RNA; Mitochondria; Mitotic; Modeling; Molecular; Mus; Oncogene Proteins; Oncogenic; Pathway interactions; Patients; Phase; Phenotype; Phosphotransferases; Play; Progesterone Receptors; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-myc; RNA Interference; Reporting; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; Writing; base; cellular engineering; chemical genetics; clinically relevant; combinatorial; design; effective therapy; high throughput screening; inhibitor/antagonist; insight; killings; malignant breast neoplasm; meetings; member; mouse model; novel; novel therapeutics; outcome forecast; overexpression; public health relevance; receptor; research study; small hairpin RNA; small molecule; therapeutic target; tool; transcription factor; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor xenograft; tumorigenic

DESCRIPTION (provided by applicant): No targeted therapeutic strategies are currently available against triple-negative (TN) breast cancer, the most difficult-to-treat form of breast cancer, which does not overexpress human epidermal growth factor receptor 2 (HER2) and lacks the expression of the estrogen and progesterone receptors. Thus, there is an urgent need in deepening our understanding of this aggressive breast cancer subtype and identifying clinically relevant targets for therapeutic intervention. We have recently discovered that an oncogenic transcription factor MYC as well as the MYC-dependent signaling pathways are significantly up-regulated in primary human triple-negative breast tumors. In addition, we found that MYC activation is associated with patients¿ poor prognosis suggesting that the MYC pathways may play a fundamental role in driving the formation of these aggressive tumors. How can we kill MYC-driven TN tumors? Because MYC is a transcription factor, rationally designed small molecule inhibitors that can directly inhibit its activity are not available for clinical use An alternative approach in selectively killing MYC-driven tumors is to exploit the existence of "synthetic-lethal" interactions. Our group previously took a cell cycle-biased approach and discovered that inhibition of the mitotic kinase cyclin-dependent kinase (CDK) 1 resulted in apoptosis in cells engineered to overexpress MYC. The mechanism of such cell death involved an up-regulation of a pro-apoptotic BCL-2 family member BIM. We subsequently used this approach to treat TN cell lines and xenograft tumors with elevated MYC expression. These observations suggest that MYC-dependent synthetic-lethal interactions exist, and importantly, can be targeted to selectively kill MYC-driven tumors. Aim 1 of this proposed research will further study the clinical potential of small molecule CDK inhibition against MYC-driven TN cancers particularly in combination with clinical inhibitors of anti-apoptotic BCL-2 members. This is based on our novel hypothesis that, because CDK inhibition up-regulates BIM and activates mitochondrial intrinsic pathway, the combined use of the inhibitors for CDK and anti-apoptotic BCL-2 family members may significantly enhance the rate of cell death. Aim 2 will characterize a newly discovered synthetic-lethal interaction between MYC activation and inhibition of Pim1, a non-essential, kinase previously shown to genetically interact with MYC. Aim 3 will conduct a high-throughput small molecule screen to identify potential lead molecules capable of inducing MYC-dependent synthetic lethality in mammary cells. We will carry out these experiments using a combination of model human mammary epithelial cells, genetically defined cancer cell lines, and a panel of novel human-in-mouse orthotopic tumor grafts models. If successful, the proposed research will not only expand our knowledge on MYC biology but will also provide novel therapeutic concepts to be tested again patients with TN tumors.

描述（由申请人提供）：目前尚无针对三阴性 (TN) 乳腺癌的靶向治疗策略，三阴性 (TN) 乳腺癌是最难治疗的乳腺癌形式，不会过度表达人表皮生长因子受体 2 (HER2) 和缺乏雌激素和孕激素受体的表达，因此，迫切需要加深我们对这种侵袭性乳腺癌亚型的了解，并确定临床相关的治疗干预靶点。 MYC 以及 MYC 依赖性信号通路在原发性人类三阴性乳腺肿瘤中显着上调。此外，我们发现 MYC 激活与患者相关。预后不良表明 MYC 通路可能在驱动这些侵袭性肿瘤的形成中发挥根本作用，我们如何杀死 MYC 驱动的 TN 肿瘤？因为 MYC 是一种转录因子，所以合理设计的小分子抑制剂可以直接抑制其活性。无法用于临床使用选择性杀死 MYC 驱动的肿瘤的另一种方法是利用“合成致死”相互作用的存在，我们的小组之前采用了一种偏向细胞周期的方法，并发现了对 MYC 驱动肿瘤的抑制。有丝分裂激酶细胞周期蛋白依赖性激酶 (CDK) 1 导致过表达 MYC 的细胞发生凋亡，这种细胞死亡的机制涉及促凋亡 BCL-2 家族成员 BIM 的上调。 MYC 表达升高的 TN 细胞系和异种移植肿瘤表明存在 MYC 依赖性合成致死相互作用，并且重要的是，可以选择性地杀死 MYC 驱动的肿瘤。这项拟议研究的第 1 项将进一步研究小分子 CDK 对抗 MYC 驱动的 TN 癌症的临床潜力，特别是与抗凋亡 BCL-2 成员的临床抑制剂联合使用。这是基于我们新的抑制假设，因为 CDK 抑制作用增强。 -调节BIM并激活线粒体内在途径，CDK抑制剂和抗凋亡BCL-2家族成员的联合使用可能会显着提高细胞死亡率，这是新发现的Aim 2的特征。 MYC 激活和 Pim1 抑制之间的合成致死相互作用，Pim1 是一种非必需激酶，之前显示与 MYC 存在遗传相互作用，Aim 3 将进行高通量小分子筛选，以鉴定能够诱导 MYC 依赖性合成致死的潜在先导分子。我们将使用人类乳腺上皮细胞模型、基因定义的癌细胞系和一组新型人鼠原位肿瘤移植物的组合来进行这些实验。如果成功，拟议的研究不仅将扩展我们对 MYC 生物学的了解，还将提供新的治疗概念，供 TN 肿瘤患者再次测试。